Equivariant Flexible Modeling of the Protein–Ligand Binding Pose with Geometric Deep Learning

Flexible modeling of the protein–ligand complex structure is a fundamental challenge for in silico drug development. Recent studies have improved commonly used docking tools by incorporating extra-deep learning-based steps. However, such strategies limit their accuracy and efficiency because they retain massive sampling pressure and lack consideration for flexible biomolecular changes. In this study, we propose FlexPose, a geometric graph network capable of direct flexible modeling of complex structures in Euclidean space without the following conventional sampling and scoring strategies. Our model adopts two key designs: scalar-vector dual feature representation and SE(3)-equivariant network, to manage dynamic structural changes, as well as two strategies: conformation-aware pretraining and weakly supervised learning, to boost model generalizability in unseen chemical space. Benefiting from these paradigms, our model dramatically outperforms all tested popular docking tools and recently advanced deep learning methods, especially in tasks involving protein conformation changes. We further investigate the impact of protein and ligand similarity on the model performance with two conformation-aware strategies. Moreover, FlexPose provides an affinity estimation and model confidence for postanalysis.